Prefrontal dopaminergic receptor abnormalities and executive functions in Parkinson's disease

The main pattern of cognitive impairments seen in early to moderate stages of Parkinson's disease (PD) includes deficits of executive functions. These nonmotor complications have a significant impact on the quality of life and day‐to‐day activities of PD patients and are not effectively managed by current therapies, a problem which is almost certainly due to the fact that the disease extends beyond the nigrostriatal system. To investigate the role of extrastriatal dopamine in executive function in PD, PD patients and a control group were studied with positron‐emission‐tomography using a high‐affinity dopamine D2/D3 receptor tracer, [¹¹C]FLB‐457. All participants were scanned twice while performing an executive task and a control task. Patients were off medication for at least 12 h. The imaging analysis revealed that parkinsonian patients had lower [¹¹C]FLB‐457 binding than control group independently of task conditions across different brain regions. Cognitive assessment measures were positively correlated with [¹¹C]FLB‐457 binding in the bilateral dorsolateral prefrontal cortex and anterior cingulate cortex only in control group, but not in PD patients. Within the control group, during the executive task (as compared to control task), there was evidence of reduced [¹¹C]FLB‐457 binding (indicative of increased dopamine release) in the right orbitofrontal cortex. In contrast, PD patients did not show any reduction in binding during the executive task (as compared with control task). These findings suggest that PD patients present significant abnormalities in extrastriatal dopamine associated with executive processing. These observations provide important insights on the pathophysiology of cognitive dysfunction in PD. Hum Brain Mapp, 2013. © 2012 Wiley Periodicals, Inc.     

Strategies for studying the neurochemical substrates of drug reinforcement in rodents

1. 1. Results from three different experimental paradigms for studying drug reinforcement are reviewed.

2. 2. Rate-increasing effects of amphetamine on intracranial self-stimulation are abolished by lesions to ascending dopamine neurons.

3. 3. Rate-increasing effects of intracranial microinjection of opioids on self-stimulation are localized to the vicinity of dopamine cell bodies in the ventral tegmentum.

4. 4. Conditioned reinforcement produced with intracranial microinjection of opioids into the ventral tegmental area is blocked by the dopamine antagonist haloperidol and lesions to ascending dopamine pathways.

5. 5. Intravenous self-administration of cocaine is blocked by intracerebral microinjection of spiroperidol into the nucleus accumbens but not into the caudate nucleus.

6. 6. Ascending dopamine neurons appear to mediate some of the reinforcing properties of both psychomotor stimulants and opioids.

Genetic and neurochemical modulation of prefrontal cognitive functions in children

OBJECTIVE: The catechol O-methyltransferase (COMT) gene affects how long dopamine acts in the prefrontal cortex. The Methionine polymorphism, which results in a slower breakdown of prefrontal dopamine, is associated with better adult prefrontal cortex function. The authors investigated the relation between the COMT gene polymorphism and cognitive performance in children. METHOD: Children were tested on cognitive tasks that depend on the dorsolateral prefrontal cortex and seem to be sensitive to the level of dopamine there (dots-mixed task), depend on that neural region but appear insensitive to its dopamine content (self-ordered pointing), and depend on other neural systems (recall memory and mental rotation). After data collection, cheek swabs were obtained from all children. DNA was extracted and genotyped for the COMT gene with polymerase chain reaction. RESULTS: Children who were homozygous for the Methionine polymorphism performed significantly better on the dots-mixed task but not on others. CONCLUSIONS: The findings provide an existence proof that genotypic differences can relate to differences in cognitive performance in typically developing children. The authors achieved a level of specificity never previously attempted; the COMT polymorphism was found to be differentially related to performance on tasks linked to the same prefrontal region by whether cognitive requirements of the tasks were sensitive to the level of dopamine found. These results challenge accepted notions that since dopamine is important for some cognitive functions dependent on the prefrontal cortex, it is important for all. The differential sensitivity of distinct cognitive abilities to specific neurotransmitters may make possible targeted pharmacological interventions.     

The neural substrates of cognitive empathy

Neuroscientific research has consistently found that the perception of an affective state in another activates the observer's own neural substrates for the corresponding state, which is likely the neural mechanism for "true empathy." However, to date there has not been a brain-imaging investigation of so-called "cognitive empathy", whereby one "actively projects oneself into the shoes of another person," imagining someone's personal, emotional experience as if it were one's own. In order to investigate this process, we conducted a combined psychophysiology and PET and study in which participants imagined: (1) a personal experience of fear or anger from their own past; (2) an equivalent experience from another person as if it were happening to them; and (3) a nonemotional experience from their own past. When participants could relate to the scenario of the other, they produced patterns of psychophysiological and neuroimaging activation equivalent to those of personal emotional imagery, but when they could not relate to the other's story, differences emerged on all measures, e.g., decreased psychophysiological responses and recruitment of a region between the inferior temporal and fusiform gyri. The substrates of cognitive empathy overlap with those of personal feeling states to the extent that one can relate to the state and situation of the other.     

Phonological dyslexia and dysgraphia: cognitive mechanisms and neural substrates

To examine the validity of different theoretical assumptions about the neuropsychological mechanisms and lesion correlates of phonological dyslexia and dysgraphia, we studied written and spoken language performance in a large cohort of patients with focal damage to perisylvian cortical regions implicated in phonological processing. Despite considerable variation in accuracy for both words and non-words, the majority of participants demonstrated the increased lexicality effects in reading and spelling that are considered the hallmark features of phonological dyslexia and dysgraphia. Increased lexicality effects were also documented in spoken language tasks such as oral repetition, and patients performed poorly on a battery of phonological tests that did not involve an orthographic component. Furthermore, a composite measure of general phonological ability was strongly predictive of both reading and spelling accuracy, and we obtained evidence that the continuum of severity that characterized the written language disorder of our patients was attributable to an underlying continuum of phonological impairment. Although patients demonstrated qualitatively similar deficits across measures of written and spoken language processing, there were quantitative differences in levels of performance reflecting task difficulty effects. Spelling was more severely affected than reading by the reduction in phonological capacity and this differential vulnerability accounted for occasional disparities between patterns of impairment on the two written language tasks. Our findings suggest that phonological dyslexia and dysgraphia in patients with perisylvian lesions are manifestations of a central or modality-independent phonological deficit rather than the result of damage to cognitive components dedicated to reading or spelling. Our results also provide empirical support for shared-components models of written language processing, according to which the same central cognitive systems support both reading and spelling. Lesion-deficit correlations indicated that phonological dyslexia and dysgraphia may be produced by damage to a variety of perisylvian cortical regions, consistent with distributed network models of phonological processing.     

Prefrontal executive function syndromes in children

"Executive function" is a term describing the processes required for conscious control of thought, emotion, and action that are central to the management of one's day-to-day life. Executive function is subserved by the prefrontal cortex and related subcortical structures. Disorders affecting the prefrontal cortex-subcortical system are numerous and heterogeneous, but contemporary research has begun to elucidate the mechanisms and consequences of dysfunction in various subsystems with increasing specificity. Prefrontal executive dysfunction results in impaired regulation of cognition, attention, behaviors, arousal, and emotion, all of which have serious and pervasive consequences for functioning across the life span. These executive function deficits are typically difficult to treat, ameliorate, or remediate and require sensitive handling by caretakers. Executive dysfunction can arise as a consequence of many different factors (metabolic, genetic, certain types of epilepsy, cerebral dysgenesis, prematurity, traumatic brain injury, hypoxia, and toxic exposure). The present review delineates the features of prefrontal executive function deficits in children and proposes a roadmap for their diagnosis, treatment, and management.     

Memory and executive functions in multiple sclerosis: preliminary findings with a cognitive battery

Twenty one MS patients suffering from a relapsing-remitting (four patients), a secondary progressive (12 patients) or a primary progressive form of the disease (five patients) were assessed using a cognitive battery specifically devoted to executive and memory processes. Results showed that, patients without significant depressive state evaluated by the MADR scale, exhibited significant impairments in executive processes, working, episodic and procedural memories whereas short term memory, language and global intellectual efficiency were normal. The preliminary data suggest an impairment of encoding, a process previously underestimated in this disease. In addition, the battery was easily administered to the patients and relevant for the cognitive assessment of MS.     

Prefrontal neurons in networks of executive memory

The neuronal networks of the frontal lobe that represent motor or executive memories are probably the same networks that cooperate with other cerebral structures in the temporal organization of behavior. The prefrontal cortex, at the top of the perception-action cycle, plays a critical role in the mediation of contingencies of action across time, an essential aspect of temporal organization. That role of cross-temporal mediation is based on the interplay of two short-term cognitive functions: one retrospective, of short-term active perceptual memory, and the other prospective, of attentive set (or active motor memory). Both appear represented in the neuronal populations of dorsolateral prefrontal cortex. At least one of the mechanisms for the retention of active memory of either kind seems to be the reentry of excitability through recurrent cortical circuits. With those two complementary and temporally symmetrical cognitive functions of active memory for the sensory past and for the motor future, the prefrontal cortex seems to secure the temporal closure at the top of the perception-action cycle.     

Intraoperative assessment of cognitive and executive functions in patients with brain tumors

BACKGROUND AND PURPOSE: The aim of this paper was to evaluate the usefulness of selected methods of intraoperative neuropsychological assessment. In order to investigate the influence of the direct cortical stimulation and tumor resection on the patients' intraoperative performance, we examined selected areas of cerebral cortex involved in cognitive activity in patients undergoing awake craniotomy for brain tumors. MATERIAL AND METHODS: The analyzed group consisted of 21 patients (11 men, 10 women) with tumors located in eloquent areas of the left hemisphere. All patients had intact understanding of speech and relatively minor neurological deficits. We applied both experimental methods as well as certain standardized tests (WAIS-R, AVLT) for the investigation of verbal and nonverbal functions. The tests were performed during direct cortical stimulation and tumor resection, and also before and one week after the operation. RESULTS: Verbal areas were identified in 10 patients, sensorimotor strip in 3, whereas both of them in 3. Even though in 5 out of 21 subjects we were unable to identify the eloquent cortex, there was no difference between pre- and postoperative assessment in these patients. Similarly, there was no statistically significant difference in pre- and postoperative tests among patients with successful cortical mapping. CONCLUSIONS: We showed that the presented methods of intraoperative assessment of cognitive activity were useful and appropriate for the identification of the eloquent areas of the brain.     

Physical activity and executive functions in the elderly with mild cognitive impairment

The primary goal of the present study was to examine whether in the elderly with mild cognitive impairment (MCI), the effect of physical activity measured directly following treatment, was reflected in an improvement in cognitive functioning in general or in executive functions (EF) in particular. Secondly, this study aimed to compare the effectiveness of two types of intervention, with varying intensities: walking and hand/face exercises. Forty-three frail, advanced elderly subjects (mean age: 86) with MCI were randomly divided into three groups, namely, a walking group (n=15), a group performing hand and face exercises (n=13), and a control group (n=15). All subjects received individual treatment for 30 minutes a day, three times a week, for a period of six weeks. A neuropsychological test battery, administered directly after cessation of treatment, assessed cognitive functioning. The results show that although a (nearly) significant improvement in tasks appealing to EF was observed in both the walking group and the hand/face group compared to the control group, the results should be interpreted with caution. Firm conclusions about the effectiveness of mild physical activity on EF in the oldest old can only be drawn after studies with larger number of subjects.     

Exploring the unity and diversity of the neural substrates of executive functioning

Previous studies exploring the neural substrates of executive functioning used task-specific analyses, which might not be the most appropriate approach due to the difficulty of precisely isolating executive functions. Consequently, the aim of this study was to use positron emission tomography (PET) to reexamine by conjunction and interaction paradigms the cerebral areas associated with three executive processes (updating, shifting, and inhibition). Three conjunction analyses allowed us to isolate the cerebral areas common to tasks selected to tap into the same executive process. A global conjunction analysis demonstrated that foci of activation common to all tasks were observed in the right intraparietal sulcus, the left superior parietal gyrus, and at a lower statistical threshold, the left lateral prefrontal cortex. These regions thus seem to play a general role in executive functioning. The right intraparietal sulcus seems to play a role in selective attention to relevant stimuli and in suppression of irrelevant information. The left superior parietal region is involved in amodal switching/integration processes. One hypothesis regarding the functional role of the lateral prefrontal cortex is that monitoring and temporal organization of cognitive processes are necessary to carry out ongoing tasks. Finally, interaction analyses showed that specific prefrontal cerebral areas were associated with each executive process. The results of this neuroimaging study are in agreement with cognitive studies demonstrating that executive functioning is characterized by both unity and diversity of processes.     

Stress-induced prefrontal reorganization and executive dysfunction in rodents

The prefrontal cortex (PFC) mediates a range of higher order ‘executive functions’ that subserve the selection and processing of information in such a way that behavior can be planned, controlled and directed according to shifting environmental demands. Impairment of executive functions typifies many forms of psychopathology, including schizophrenia, mood and anxiety disorders and addiction, that are often associated with a history of trauma and stress. Recent research in animal models demonstrates that exposure to even brief periods of intense stress is sufficient to cause significant structural remodeling of the principle projection neurons within the rodent PFC. In parallel, there is growing evidence that stress-induced alterations in PFC neuronal morphology are associated with deficits in rodent executive functions such as working memory, attentional set-shifting and cognitive flexibility, as well as emotional dysregulation in the form of impaired fear extinction. Although the molecular basis of stress-induced changes in PFC morphology and function are only now being elucidated, an understanding of these mechanisms could provide important insight into the pathophysiology of executive dysfunction in neuropsychiatric disease and foster improved strategies for treatment.     

The remediation of executive functions in children with cognitive disorders: the Vygotsky-Luria neuropsychological approach

The demands of methods of effective remediation arising from the Vygotsky-Luria approach to the structure and development of higher mental functions are discussed. These demands suggest the structuring of a therapeutic interaction in accordance with the rules of the internalization process, taking into account a weak component of the child's functional systems and the emotional involvement of a child in that Interaction. In order to provide a theoretical framework for developing methods of executive function remediation, the approaches of Vygotsky and Luria, as well as modern views on the structure and development of executive functions, are discussed. The Method of Numerical Sequence is presented as an example of the application of the general principles discussed above. The Method of Numerical Sequence provides a background for following the development of successive processing, programming and planning, and can be considered as a complement to the development of the metacognitive aspects of self–regulation. This method was verified experimentally in groups of 5–8-year-old children with intellectual disability.     

The neural substrates of cognitive control deficits in autism spectrum disorders

Executive function deficits are among the most frequently reported symptoms of autism spectrum disorders (ASDs), however, there have been few functional magnetic resonance imaging (fMRI) studies that investigate the neural substrates of executive function deficits in ASDs, and only one in adolescents. The current study examined cognitive control – the ability to maintain task context online to support adaptive functioning in the face of response competition – in 22 adolescents aged 12–18 with autism spectrum disorders and 23 age, gender, and IQ matched typically developing subjects. During the cue phase of the task, where subjects must maintain information online to overcome a prepotent response tendency, typically developing subjects recruited significantly more anterior frontal (BA 10), parietal (BA 7 and BA 40), and occipital regions (BA 18) for high control trials (25% of trials) versus low control trials (75% of trials). Both groups showed similar activation for low control cues, however the ASD group exhibited significantly less activation for high control cues. Functional connectivity analysis using time series correlation, factor analysis, and beta series correlation methods provided convergent evidence that the ASD group exhibited lower levels of functional connectivity and less network integration between frontal, parietal, and occipital regions. In the typically developing group, fronto-parietal connectivity was related to lower error rates on high control trials. In the autism group, reduced fronto-parietal connectivity was related to attention deficit hyperactivity disorder symptoms.     

EpiTrack: tracking cognitive side effects of medication on attention and executive functions in patients with epilepsy

RATIONALE: Achievement of maximum seizure control with preservation or even improvement of patient's cognitive capabilities is the major aim of epilepsy therapy. EpiTrack is a brief screening tool for the tracking of cognitive side effects of antiepileptic drugs. Test selection was based on recent studies on the effects of topiramate on cognition and retrospective inspection of results from patients with antiepileptic drug (AED) side effects. METHODS: The 15-minute screening tool comprises six subtests: the Trail-Making Test (parts A and B), a test of response inhibition, digit span backward, written word fluency, and a maze test. These tests were standardized in 220 healthy subjects, 100 of whom were reevaluated after 5.3 months to obtain information on reliability and practice effects. Criterion validity was determined by correlation to other neuropsychological measures. For a first clinical evaluation, the impact of epilepsy (seizures) and medication on EpiTrack scores was evaluated cross-sectionally in 184 consecutive inpatients with chronic epilepsy. RESULTS: According to the normative data, we developed an easy scoring scheme assigning test scores on a 7-point scale. The EpiTrack is suitable for patients between 18 and 60 years of age. Age corrections were included for patients between 40 and 60 years. EpiTrack scores on subtests for both controls and patients were submitted to principal component analysis. VARIMAX rotation yielded a two-factor solution (verbal/visuo-spatial) that accounted for 63.8% of the total variance in controls. In the patient group, only one factor emerged accounting for 54.7% of variance. EpiTrack correlates with global scores of attention (r=0.85) and language (r=0.67) (P's<0.001). At a cutoff score of 25, only 2.7% of the controls were classified as impaired, while impairment was indicated in 48.4% of the patients. The score is sensitive to monthly frequency of complex partial seizures and to number of AEDs. It shows negative cognitive effects of valproate and topiramate given in mono/polytherapy. CONCLUSION: EpiTrack is a promising 15-minute screening tool for the detection and tracking of cognitive side effects of AEDs and adverse effects of seizures in patients with epilepsy. Future application will show its value in prospective follow-up studies on AED side effects.     

Prefrontal cognitive functions in stabilized first-episode patients with schizophrenia spectrum disorders: a dissociation between dorsolateral and orbitofrontal functioning

Specific prefrontal cognitive impairments have been reported in first-episode and chronic schizophrenia. We sought to investigate potential impairments in specific prefrontal cortical cognitive functions among stabilized patients with a first-episode of schizophrenia. A sample of 80 individuals with a first-episode of schizophrenia spectrum disorders and 22 healthy volunteers underwent a neurocognitive battery assessing orbitofrontal (OFC) [The Iowa Gambling Task (GT)], and dorsolateral prefrontal (DLPFC) functions (WAIS III Backward digits, verbal fluency test (FAS), and Trail Making Test). Cognitive data were obtained following stabilization of acute psychotic symptoms. Clinical symptoms after six weeks of treatment were assessed by using the SAPS and SANS scales. While there were no significant group differences in overall scores and in the profile of progress of performance along periods on the GT, patient group showed a significant impairment when performing DLPFC tasks. Only FAS score was correlated to the severity of negative symptomatology. The OFC functions are unimpaired at the early phases of psychosis and in contrast there is a significant deficit in DLPFC functions in first-episode of schizophrenia.     

The psychological, neurochemical and functional neuroanatomical mediators of the effects of positive and negative mood on executive functions

In this review we evaluate the cognitive and neural effects of positive and negative mood on executive function. Mild manipulations of negative mood appear to have little effect on cognitive control processes, whereas positive mood impairs aspects of updating, planning and switching. These cognitive effects may be linked to neurochemistry: with positive mood effects mediated by dopamine while negative mood effects may be mediated by serotonin levels. Current evidence on the effects of mood on regional brain activity during executive functions, indicates that the prefrontal cortex is a recurrent site of integration between mood and cognition. We conclude that there is a disparity between the importance of this topic and awareness of how mood affects, executive functions in the brain. Most behavioural and neuroimaging studies of executive function in normal samples do not explore the potential role of variations in mood, yet the evidence we outline indicates that even mild fluctuations in mood can have a significant influence on neural activation and cognition.